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Biomedical subjects

S Rajaraman

Publications and source records attributed to S Rajaraman.

At least 19 recordsLinked to original sources
PubMed2002

An allelic series of mutations in the kit ligand gene of mice. I. Identification of point mutations in seven ethylnitrosourea-induced Kitl(Steel) alleles.

An allelic series of mutations is an extremely valuable genetic resource for understanding gene function. Here we describe eight mutant alleles at the Steel (Sl) locus of mice that were induced with N-ethyl-N-nitrosourea (ENU). The product of the Sl locus is Kit ligand (or Kitl; also known as mast cell growth factor, stem cell factor, and Steel factor), which is a member of the helical cytokine superfamily and is the ligand for the Kit receptor tyrosine kinase. Seven of the eight ENU-induced Kitl(Sl) alleles, of which five cause missense mutations, one causes a nonsense mutation and exon skipping, and one affects a splice site, were found to contain point mutations in Kitl. Interestingly, each of the five missense mutations affects residues that are within, or very near, conserved alpha-helical domains of Kitl. These ENU-induced mutants should provide important information on structural requirements for function of Kitl and other helical cytokines.

Alleles↗
PubMed2002

An allelic series of mutations in the Kit ligand gene of mice. II. Effects of ethylnitrosourea-induced Kitl point mutations on survival and peripheral blood cells of Kitl(Steel) mice.

The ligand for the Kit receptor tyrosine kinase is Kit ligand (Kitl; also known as mast cell growth factor, stem cell factor, and Steel factor), which is encoded at the Steel (Sl) locus of mice. Previous studies revealed that Kitl(Sl) mutations have semidominant effects; mild pigmentation defects and macrocytic, hypoplastic anemia occur in heterozygous mice, and more severe pigmentation defects and anemia occur in homozygotes. Lethality also occurs in mice homozygous for severe Kitl(Sl) mutations. We describe the effects of seven new N-ethyl-N-nitrosourea (ENU)-induced Kitl(Sl) mutations and two previously characterized severe Kitl(Sl) mutations on pigmentation, peripheral blood cells, and mouse survival. Mice heterozygous for each of the nine mutations had reduced coat pigmentation and macrocytosis of peripheral blood. In the case of some of these mutations, however, red blood cell (RBC) counts, hemoglobin concentrations, and hematocrits were normal in heterozygotes, even though homozygotes exhibited severely reduced RBC counts and lethality. In homozygous mice, the extent of anemia generally correlates with effects on viability for most Kitl(Sl) mutations; i.e., most mutations that cause lethality also cause a more severe anemia than that of mutations that allow viability. Interestingly, lethality and anemia were not directly correlated in the case of one Kitl(Sl) mutation.

Alleles↗
PubMed2001

Angiogenesis in autosomal-dominant polycystic kidney disease.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is a genetic disorder that is responsible for approximately 10% of all cases of end-stage renal disease (ESRD). It is characterized by the formation of epithelial cell cysts, an increase in the extracellullar matrix, and vascular alterations believed to be the result of compression by the cysts. Our recent observations demonstrated a rich vascular network on the surface of the cysts, and thus, we postulated that angiogenesis could be a factor in the progression of ADPKD. METHODS: Kidneys removed from patients with ADPKD were studied using (1) angiographs, (2) immunostaining [factor VIII-related antigen, vascular endothelial growth factor (VEGF), VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2), metalloproteinase-2 (MMP-2), and integrin alphavbeta3], and (3) Western blot analysis and enzyme-linked immunosorbent assay. The expression of VEGF165 in ADPKD cells in culture was determined. RESULTS: There was (1) an extensive capillary network in the cyst wall of ADPKD kidneys, (2) morphological evidence of vascular malformations, (3) expression of VEGF165 in cyst cells of VEGFR-2 in endothelial cells and an absence of VEGFR-1 in endothelial cells, (4) secretion of VEGF165 by ADPKD cyst cells in culture, and (5) coexpression of matrix MMP-2 and integrin alphavbeta3 in vessels from ADPKD. CONCLUSIONS: There is angiogenesis in ADPKD. This process may be necessary for cyst cells to grow and may be responsible for increased vascular permeability facilitating fluid secretion into the cysts. Neovascularization may result in the formation of aneurysms responsible for the renal bleeding in this disease.

Angiography↗
PubMed2001

Late recurrence of lupus nephritis in a renal transplant recipient: response to mycophenolate mofetil.

Clinically significant recurrence of lupus nephritis in the renal allograft is low, with an incidence of 1 to 3%, and usually occurs within the first 6 years after transplantation. We report an unusual case of a patient with end-stage renal disease caused by lupus nephritis who received a kidney transplant from a living relative; 13 years later, the patient had a severe recurrence of diffuse proliferative lupus nephritis. The patient relapsed after receiving intravenous cyclophosphamide therapy and had a partial response to oral mycophenolate mofetil. In this report we review the risk factors for the recurrence of the systemic lupus erythematosus in the kidney graft and the anti-lupus activity of mycophenolate mofetil.

Adult↗
PubMed2000

Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients.

Previous studies have reported that approximately 10% of the patients with human immunodeficiency virus (HIV) infection develop HIV-associated nephropathy (HIVAN). However, over the last decade, morbidity and mortality as a result of HIV-1 infection has remarkably decreased with the availability of potent new antiretroviral drugs. We therefore determined the prevalence of HIVAN from autopsy data of HIV-infected patients in more recent years (1992 to 1997). Autopsy reports of 389 patients were reviewed. In reports suggestive of possible HIVAN, slides of renal tissue were retrieved and reviewed again to ensure appropriate classification. The criteria for the diagnosis of HIVAN were focal segmental glomerulosclerosis with collapse of the glomerular tuft in some glomeruli, extensive tubular ectasia, and significant tubulointerstitial disease. Of 389 autopsy reports, 54% of the patients were black, 35% were white, and 11% were Hispanic. Thirty-three percent of the patients had a history of intravenous drug abuse. The mean CD4 count of the patients was 54 +/- 91/microL (mean +/- SD). In 27 cases, typical features of HIVAN were found based on the criteria used, accounting for an overall HIVAN prevalence of 6.9% (27 of 389 autopsies). Because the overwhelming majority of these patients were black (93%), the prevalence in blacks was 12% (25 of 209 autopsies). We conclude that although mortality and morbidity from HIV infection is decreasing, HIVAN remains an important complication of HIV infection in blacks, even in recent years.

AIDS-Associated Nephropathy↗
PubMed2000

Cardiopulmonary manifestations of Henoch-Schönlein purpura.

Henoch-Schönlein purpura (HSP) is usually a mild condition involving the skin, gut, joints, and kidneys and has a good prognosis. We present a 63-year-old Hispanic man who had an unusually severe form of HSP with a fatal outcome attributable to vasculitis causing myocardial necrosis. There is only one citation in the literature of HSP-related myocardial vasculitis, which involved the right ventricle and was successfully treated with steroids. Our patient had severe HSP-related myocardial necrosis, tracheobronchitis, and nephritis. The bronchial lesions resolved, presumably because of steroid therapy. This probably is the first case of fatal myocardial necrosis related to HSP. We conclude that HSP can, in some cases, have an aggressive course. It becomes imperative to recognize the involvement of the other organ systems, such as the heart, so that appropriate therapy may be initiated. Immunosuppression may have a beneficial effect on extrarenal lesions. Controlled clinical trials are needed to establish the efficacy of such treatment.

Cardiomyopathies↗
PubMed2000

Burn and starvation increase programmed cell death in small bowel epithelial cells.

Maintenance of gut mucosal homeostasis depends on a balance between cell proliferation and cell death. Gut mucosal integrity is impaired after severe burn and during starvation. We determined the effect of burn, starvation, and the combination of both on small bowel epithelial apoptosis and proliferation. Fifty adult male Fischer 344 rats (260-300 g) received a 60% full-thickness scald burn and were randomly divided into fed and starved groups. Small intestine was taken at 12, 24, and 48 hr after injury. All animals in the 12-hr group were starved while recovering from anesthesia. Apoptosis was quantified by immunohistochemical staining (TUNEL) and mucosal proliferation was determined by bromodeoxyuridine (BrdU) incorporation. The apoptotic index was higher in burned rats compared to controls at 12 hr after burn; both these groups were starved (P < 0.05). At 24 and 48 hr after burn, apoptosis was highest in the starved groups, with no additional effects of burn (P < 0.05). Mucosal epithelial cell proliferation was not different between groups at any time point. In conclusion, burn and starvation both increase apoptosis in the small bowel mucosa; however, these effects are not additive. Apoptosis could be attenuated by enteral feeding, which delineates the importance of early enteral feeding initiation after injury to maintain mucosal integrity.

Animals↗
PubMed2000

Waterhouse-Friderichsen syndrome and bilateral renal cortical necrosis in meningococcal sepsis.

Waterhouse-Friderichsen syndrome and bilateral renal cortical necrosis (BRCN) are rare complications of meningococcal sepsis associated with high mortality rates. We describe a 20-year-old man who presented with a 1-day history of fever, chills, malaise, and vomiting. He collapsed in the emergency room, requiring mechanical ventilation and intravenous vasopressors for resuscitation. He was noted to be anuric, and computed tomography showed adrenal hemorrhage and BRCN. Blood cultures later confirmed Neisseria meningitidis sepsis, and a biopsy confirmed renal cortical infarction. The patient was treated aggressively with intravenous antibiotics, corticosteroids, and immunoglobulins, in addition to plasmapheresis, dialysis, and supportive measures. He recovered his adrenal function and was discharged from the hospital, but he remains dialysis dependent. To our knowledge, this is the first reported case of concomitant Waterhouse-Friderichsen syndrome and BRCN in a patient with meningococcal sepsis.

Adult↗
PubMed2000

Response of keratinocytes from normal and psoriatic epidermis to interferon-gamma differs in the expression of zinc-alpha(2)-glycoprotein and cathepsin D.

Psoriasis is a T cell-mediated inflammatory disease characterized by hyperproliferation and by aberrant differentiation. We found cathepsin D and zinc-alpha(2)-glycoprotein, two catalytic enzymes associated with apoptosis and desquamation, to be present in the stratum corneum of the normal epidermis but absent from the psoriatic plaque. Psoriasis is characterized by an altered response to interferon-gamma (IFN-gamma), including the induction of apoptosis in normal but not in psoriatic keratinocytes, often with opposite effects on gene expression of suprabasal proteins. We found that IFN-gamma binding and signaling were attenuated in psoriasis: The IFN-gamma receptor, the signal transducer and activator of transcription STAT-1, and the interferon regulatory factor IRF-1 were strongly up-regulated by IFN-gamma in normal keratinocytes, but not in psoriatic ones. IFN-gamma strongly up-regulated the expression of the catalytic enzymes cathepsin D and zinc-alpha(2)-glycoprotein in normal keratinocytes but down-regulated them in psoriatic ones; the reverse was true of the apoptotic suppressor bcl-2. We believe that the aberrant response to IFN-gamma plays a central role in the pathophysiology of psoriasis, particularly the disruption of apoptosis and desquamation.

Cathepsin D↗
PubMed2000

Increased small bowel epithelial turnover in interleukin-1 receptor knockout mice.

OBJECTIVE: To determine whether interleukin-1 (IL-1) affects the cellular homeostasis of small bowel mucosa, the authors studied apoptosis and proliferation in small bowel epithelium in two groups of C57 mice: an IL-1 receptor knockout group, and a control wild-type group. SUMMARY BACKGROUND DATA: Gut mucosal integrity is maintained by a balance of cell proliferation and cell death. Recent reports suggest that IL-1, a proinflammatory cytokine, increases cell death by apoptosis in some epithelial cells. METHODS: Twenty-four male C57BL6 IL-1 receptor (type I) knockout mice were killed, and small bowel was removed for study. Twenty-four wild-type mice (C57-BL6) served as controls. Body weights, bowel length, and mucosal morphology were examined for phenotypic differences. Apoptosis was quantified by terminal deoxyuridine nick-end labeling (TUNEL) immunohistochemical staining and cellular proliferation by proliferation cell nuclear antigen staining. Whole mucosal protein was analyzed for nuclear factor-kappaB expression. Groups were analyzed by t test. RESULTS: The absence of IL-1 type I receptor in knockout mice was verified by reverse transcriptase-polymerase chain reaction. IL-1 receptor null mice were larger than wild-type controls, with a longer small bowel; however, the index of small bowel length to total body weight did not differ between groups. The percentage of apoptotic cells was higher in IL-1 receptor null mice than in wild-type mice; the proliferation index also increased. Mucosal height and other measures of mucosal morphology were not different. Genotypic absence of IL-1 receptors was associated with decreased expression of nuclear factor-kappaB in whole mucosal protein extracts. CONCLUSIONS: Both apoptosis and proliferation increased in gut epithelial cells of mice without IL-1 receptors, suggesting increased cell turnover with no change in net balance. This model represents an opportunity to examine potential mechanisms of gut epithelial turnover in vivo, under both normal conditions and in conditions of mucosal proliferation and atrophy.

Animals↗
PubMed2000

Acute pancreatitis results in induction of heat shock proteins 70 and 27 and heat shock factor-1.

Heat shock proteins (HSPs) 70 and 27 are stress-responsive proteins that are important for cell survival after injury; the expression of these HSPs is regulated primarily by the transcription factor heat shock factor-1 (HSF-1). The purpose of this study was to determine the effect of acute pancreatitis on pancreatic HSPs (70, 27, 60, and 90) expression and to assess potential mechanisms for HSP induction using a murine model of cerulein-induced pancreatitis. We found an increase of both HSP70 and HSP27 levels with expression noted throughout the pancreas after induction of pancreatitis. HSP60 and HSP90 levels were constitutively expressed in the pancreas and did not significantly change with acute pancreatitis. HSF-1 DNA binding activity increased in accordance with increased HSP expression. We conclude that acute pancreatitis results in a marked increase in the expression of HSP70 and HSP27. Furthermore, the induction of HSP70 and HSP27 expression was associated with a concomitant increase in HSF-1 binding activity. The increased expression of both HSP70 and HSP27 noted with pancreatic inflammation may confer a protective effect for the remaining acini after acute pancreatitis.

Acute Disease↗
PubMed2000

Case report. Intestinal infarction due to vascular catastrophe in an HIV-infected patient.

A 40-year-old HIV-infected woman developed nausea, vomiting, and epigastric pain and died following her third dose (per study protocol) of interleukin (IL)-2. Her HIV infection was diagnosed in 1996. Her last CD4 cell count was 390/microL, and her viral load was negligible (as of November 28, 1998). She had no known general risk factors for thrombosis other than HIV infection, injection drug abuse, and antiretroviral therapy with indinavir. Abdominal films showed no sign of mechanical obstruction but a generalized gas distention of the bowel, which was suggestive of paralytic ileus. Autopsy revealed dilation of the small bowel with extensive necrosis and hemorrhage involving all the segments. The superior and inferior mesenteric arteries revealed severe atherosclerosis. The stenotic celiac artery was occluded by a recent thrombus at the aortic ostium. Clinicians need to be aware of the potential for thrombosis and accelerated atherosclerosis in HIV-infected patients. Both injection drug abuse and protease inhibitors, such as indinavir, have been shown to be risk factors for thrombosis. However, it is likely IL-2 contributed to the severe thrombosis in this patient, although definitive proof is lacking. An acute awareness of intestinal infarction in HIV-infected patients is warranted.

Adult↗
PubMed2000

A survival study of cervical cancer in Chennai, India.

A total of 4304 cervical cancer cases registered during 1982-89 in Chennai registry, India, were analyzed. Relative survival at 1, 3 and 5 years were 90%, 72% and 60% respectively. Age at diagnosis and extent of disease emerged as statistically significant prognostic factors (p<0.001). Five-fold higher risk of death was seen among those above 64 years vs. <45 years and those with distant metastasis vs. localized disease at diagnosis. Cancer control programs focusing on health education would motivate women to attend hospital at an early stage of disease for better survival.

Adult↗
PubMed1999

Cutaneous burn increases apoptosis in the gut epithelium of mice.

BACKGROUND: Gut mucosal homeostasis depends on a balance between cell proliferation and cell death. After cutaneous burn injury, gut mucosal weight has been shown to decrease. This decrease in weight was paradoxically associated with an increase in gut proliferative factors. For mucosal weight to decrease in the presence of increased proliferation, there must be an even greater increase in cell death. We postulate that cutaneous burn injury causes an increase in gut epithelial cell death primarily by apoptosis. STUDY DESIGN: We produced a 30% full-thickness scald burn in the dorsum of anesthetized male C57BL6 mice and collected the proximal small bowel at 12, 24, 36, 48, and 60 hours after injury. Sham burned animals served as controls. Apoptosis and proliferation were measured by immunohistochemical assays (terminal deoxyuridine nick-end labeling for apoptosis and proliferative cell nuclear antigen assay for proliferation). Apoptosis was also measured by ELISA for cytoplasmic histone-associated DNA fragments. Mucosal height was determined on histologic sections. The two groups were compared at each time point using Wilcoxon two-sample test and t-test with Bonferroni's correction where appropriate. RESULTS: The percentage of apoptotic cells (number of cells stained by terminal deoxyuridine nick-end labeling per 100 villus cells) was significantly higher at 12, 24, and 48 hours after injury. This increase was corroborated by an increase in the ELISA at 12 hours. Proliferation as measured by immunostaining for proliferative cell nuclear antigen significantly increased at 12, 24, 48, and 60 hours. Mucosal height as a gross measure of mucosal atrophy was not different between the groups. CONCLUSIONS: We have shown an increase in apoptosis coupled with an increase in proliferation after a burn injury. These results imply an increase in cell turnover in the gut epithelial cells after a burn. Impaired bowel function has been demonstrated repeatedly after burn injury, and this increase in cell turnover may be related.

Animals↗
PubMed1999

Is the prevalence of HIV-associated nephropathy decreasing?

Initial reports have suggested that approximately 10% of patients with HIV-infection develop HIV-associated nephropathy (HIVAN). It has also been predicted that by the end of the decade, HIVAN is likely to become a third leading cause of end-stage renal disease (ESRD) in African-Americans between the ages of 20-64 years. As the morbidity and mortality from HIV-infection has decreased in the last few years, it is possible that prevalence of HIVAN is also changing. We therefore screened HIV-1-infected patients followed in our hospital for HIVAN. A screening urinalysis was performed in 557 HIV-1-infected adult patients between March and May 1998. Of these, 252 were outpatients and 305 were Texas Department of Criminal Justice inmates (TDCJI). Demographic and laboratory data of these patients was obtained from the HIV patients' database. Fifty percent of the patients were African-American, 36.6% were Caucasian and 12. 7% were Hispanic. The mean age of patients was 37 +/- 8 years. Seventy-nine percent of the patients were males and a history of intravenous drug abuse (IVDA) was present in 28%. Twenty-three percent of the patients were concomitantly infected with hepatitis C virus, 4.1% were positive for hepatitis B surface antigen, and rapid plasma reagin test for syphilis was positive in 9.1%. In 38 patients who had more than 100 mg/dl (2+) proteins on screening urinalysis, total urinary proteins were quantitated by collecting 24 h urine specimens. Fifteen of these patients had urinary proteins more than 1.5 g/day (12 patients >3.5 g/24 h and 3 patients >1.5 g/24 h). A renal biopsy was done in 14 of these patients and clinical diagnosis of HIVAN was made in one patient who refused biopsy. Renal biopsies revealed HIVAN [9], diabetic nephropathy [2], membranoproliferative glomerulonephritis [2], Fibrillary glomerulonephritis [1]. All 10 patients (5 TDCJI and 5 outpatients) with HIVAN were African-American. Two of these 10 patients had a history of IVDA and another two were concomitantly infected with hepatitis C virus. The plasma viral load (Pvl) and total CD4 count was not different in patients with or without HIVAN [(Pvl log 10.05 +/- 1.39 vs. 9.9 +/- 2.18 copies/ml, p = 0.78) (CD4: 187 +/- 192 vs. 288 +/- 249 cells/microl, p = 1.17) mean +/- SD]. We conclude that in our HIV-infected population HIVAN exclusively affected African-Americans and the prevalence in them was 3.5%.

AIDS-Associated Nephropathy↗
PubMed1999

Stimulatory actions of insulin-like growth factor-I and transforming growth factor-alpha on intestinal neurotensin and peptide YY.

Proliferation of the gastrointestinal mucosa is stimulated by the growth factors, insulin-like growth factor-I (IGF-I) and transforming growth factor-alpha (TGF-alpha), or the closely related epidermal growth factor (EGF), as well as the gastrointestinal hormones, gastrin, neurotensin (NT), and peptide YY (PYY). The stimulatory actions of these growth factors or gastrointestinal hormones on the gastrointestinal mucosa may be direct or mediated in part by gastrointestinal peptides or the growth factors, respectively. The purpose of these studies therefore was to examine the effects of IGF-I and TGF-alpha on stomach gastrin and intestinal NT and PYY gene expression [i.e. messenger RNA (mRNA), peptide levels] and secretion. Mice were given recombinant human IGF-I (3, 6 mg/kg BW/day x 14 days). Transgenic mice with the rat TGF-alpha gene linked to a metallothionein promoter were used as a model of chronic TGF-alpha excess. IGF-I and TGF-alpha did not affect gastrin gene expression. Steady-state intestinal NT and PYY mRNA and peptide levels were elevated in a dose-related manner by IGF. TGF-alpha also increased intestinal expression of NT and PYY peptide, but not mRNA levels. Basal serum levels of PYY were elevated by IGF-I and TGF-alpha. IGF-I and TGF-alpha did not increase intestinal chromogranin A (CGA) gene expression, a marker of endocrine cells, or the density of PYY-containing cells in the colon, indicating that the elevations in intestinal gut peptide gene expression by IGF-I and TGF-alpha are not due simply to an increased number of enteroendocrine cells. IV infusion of EGF also stimulated release of PYY in the dog. Together, these findings indicate that IGF-I and TGF-alpha may cause secretion of gut hormones and exert a major upregulatory influence on the regulation of intestinal peptide hormone homeostasis.

Animals↗
PubMed1999

Wischnewski ulcers and acute pancreatitis in two hospitalized patients with cirrhosis, portal vein thrombosis, and hypothermia.

Accidental hypothermia has been described in the forensic literature but reports of occurrence in hospitalized patients are rare. Associated anatomic lesions include acute hemorrhagic pancreatitis and characteristic acute gastric ulcers termed Wischnewski ulcers. We report here two patients with cirrhosis and ascites; one also had hepatocellular carcinoma. Portal vein thrombosis, acute hemorrhagic pancreatitis and Wischnewski ulcers were present in both. The clinical records documented hypothermia that progressed over several days. Temperature nadirs of 31.0 degrees C (87.8 degrees F) and 32.2 degrees C (90.0 degrees F) were recorded in each patient, respectively, one day before death, although each transiently reached temperatures that did not register on standard monitoring devices. This is the first report that chronicles antemortem body temperatures in hypothermic patients with Wischnewski ulcers and pancreatitis at autopsy. Also, the association of these findings with portal vein thrombosis and cirrhosis has not been previously described. We discuss this constellation of findings with regard to possible mechanistic interrelations.

Acute Disease↗